Recent advances on the molecular pathogenesis of prion diseases

Prion diseases continue to fascinate scientists from different disciplines since the discovery that a misfolded prion protein can act as an infectious agent. Infectious prions have caused epidemics, including kuru in humans, cervid chronic wasting disease, bovine spongiform encephalopathy (BSE) or “mad cow disease,” and most recently, camel prion disease, which was identified in 2018 1. In Kuru, spread of the disease occurred from the ingestion of prion‐infected, dead relatives as part of mourning practices, whereas in chronic wasting disease, prions may be transmitted not only through ingesting prion‐contaminated food, but also by exposure to a prion‐contaminated environment 12, 13. In all instances, prions hold structural properties that cause different disease presentations, which can be passed on to another individuals 21. However, the most common form of human prion disease, sporadic Creutzfeldt‐Jakob disease, is not caused by exposure to infectious prions but occurs as a rare disease from unknown causes 23. In all instances, prions cause a neurodegenerative disease with neuropathological and mechanistic overlap with other protein misfolding disorders, such as Alzheimer’s or Parkinson’s disease 9. Interestingly, a great number of neurodegenerative diseases spread through the brain as prions do, yet some obvious differences in disease characteristics have to considered (Table 1).

Table 1.

Similarities and differences between bona fide prion diseases and other dementias. A, most likely incomplete and highly subjective, list of features usually attributed to prion diseases, some of which are seen in a wide range of dementias.

Although our understanding of prion disease has experienced a boost in the last 10 years, there are gaps in our understanding of the molecular basis of this complex disease 18. An incomplete list of these unchartered territories include (i) the structure of the prion aggregate and how this relates to the spread of prions within a host and also from host to host, (ii) the need to detect prions or disease biomarkers ante‐mortem in order to establish and test therapies and (iii) an integrated view of the mechanisms underlying prion neurotoxicity. In this issue of Brain Pathology, we have assembled experts in the field to report on the state of the art developments in human prion diseases, animal prion diseases and on the mechanisms of prion neurotoxicity. The mini‐symposium is further completed by one original article reporting on the influence of microRNAs in regulating the prion protein 17 and by one original article proposing a molecular mechanism to explain the extraordinary susceptibility of bank voles to prion infection 8.

One thing prion scientists, especially the ones involved in neuropathological characterization of the disease, are particularly proud of, is the categorization of disease subtypes based on histological, genetic and biochemical criteria. In the review by Piero Parchi and colleagues, this categorization‐system is introduced, and novel aspects relevant not only to prion scientists but also to the wider neuropathological community concerning co‐pathology or cross‐seeding phenomena are elucidated 2.

Animal prion diseases continue to emerge, recently with variants of scrapie and BSE, a camel prion disease in Algeria 1 and chronic wasting disease in Scandinavian wild reindeer 3 and moose 19. What are the risks for animal prions infecting humans? Houston and Andreoletti summarize the history, epidemiology and pathogenesis of the animal prion diseases, and review research designed to estimate the risk of human infection 7. The authors also highlight the limitations of experimental models and consider the uncertainties for zoonotic transmission that still remain, ultimately emphasizing the importance of preventing human exposure to prions.

The pathologic hallmarks of prion disease include spongiform degeneration, gliosis, aggregated prion protein and neuronal loss, yet we are only beginning to understand how toxic signaling through the prion protein can induce neuronal death. David Harris and colleagues note the obstacles that have hampered investigations of neurotoxicity, most notably the lack of an in vitro model system that recapitulates features of neuronal degeneration. They review new experimental systems used in recent years to model prion neurotoxicity in order to define the signaling pathways activated by prion aggregates 10. They also consider structural modifications in the prion protein that can trigger neurotoxic sequelae. Finally, the authors discuss missing links in the neurotoxic signaling pathway and note opportunities to identify novel drug targets to mitigate toxic signaling, which may also have relevance for other neurodegenerative diseases.

In summary, this mini‐symposium is as interesting and diverse as prion diseases, and we hope the readers enjoy reading the articles as much as we have.